CN116284871A - 一种高粘附性壳聚糖基水凝胶及其制备方法与应用 - Google Patents
一种高粘附性壳聚糖基水凝胶及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种高粘附性壳聚糖基水凝胶及其制备方法与应用。本发明采用的主要原料为天然多糖壳聚糖和作为生物缓冲液的TMG,原料来源丰富,具有优良生物相容性和生物可降解性。采用TMG修饰壳聚糖,通过氢键交联形成水凝胶,得到以天然多糖基为原料的水凝胶。所得到的水凝胶通过与皮肤表面形成氢键作用,从而赋予水凝胶优异的粘附性能,可用于伤口敷料和急性止血材料。除皮肤表面外,本发明所得水凝胶在玻璃、金属等材料表面同样表现出优异的粘附性能,在粘合剂方面具有潜在的应用前景。
Description
技术领域
本发明涉及高分子材料领域,特别涉及一种高粘附性壳聚糖基水凝胶及其制备方法与应用。
背景技术
急性创伤、外科手术和慢性疾病造成的皮肤创伤仍然是人类面临的巨大挑战。设计有效的伤口敷料已经成为现代医疗系统中迫切需要解决的问题。与其他伤口粘附剂相比,水凝胶粘附剂具有以下优点:(1)与原生细胞外基质相似,能够更好地维持组织功能,促进细胞迁移;(2)优良的细胞、药物和生物活性载体;(3)水分含量高,能够维持湿润的伤口环境。因此,水凝胶粘附剂广泛应用于不同类型的创面愈合。水凝胶是一种由高分子聚合物构成的三维网络结构,用天然多糖及其衍生物所构建的水凝胶,具有独特的生物活性,生物相容性好,免疫反应低,易于物理化学改性、来源丰富、价格低廉等优点,广泛应用于止血和创面愈合。常用来制备粘附性水凝胶的天然多糖有壳聚糖、透明质酸、纤维素、海藻酸盐、葡聚糖、硫酸软骨素、普鲁兰多糖等。
壳聚糖是一种由甲壳素在碱性环境中去乙酰化得到的碱性多糖,在自然界中含量丰富、容易得到。壳聚糖中容易获得游离氨基,携带一个正电荷,可以与许多带负电荷的物质反应。壳聚糖具有生物降解性、生物相容性、粘附性、抗菌性和低毒性等特点,近年来被广泛研究应用于药物递送、抗菌涂层、给药系统、伤口辅料和软骨再生等方面。与此同时,壳聚糖基粘附性水凝胶的研究仍面临着巨大挑战,如壳聚糖的低溶解度和溶液的高粘度导致生成的壳聚糖物理网络脆而弱等,所以采用合适的物质对壳聚糖进行改性以提高其力学性能和粘附性能仍然是一项艰巨的任务。
发明内容
本发明的目的在于克服现有技术的缺点与不足,提供一种高粘附性壳聚糖基水凝胶的制备方法。该制备方法主要通过TMG与壳聚糖之间形成酰胺化反应,借助多重氢键作用交联形成TMG修饰的高粘附性壳聚糖基水凝胶。
本发明的另一目的在于,提供上述制备方法制备得到的高粘附性壳聚糖基水凝胶,该水凝胶生物相容性好,粘附性能好。
本发明的再一目的在于,提供上述高粘附性壳聚糖基水凝胶的应用。
本发明的目的通过下述技术方案实现:
一种高粘附性壳聚糖基水凝胶的制备方法,包括如下步骤:
(1)壳聚糖醋酸溶液的制备
将壳聚糖溶于醋酸溶液中,搅拌,使壳聚糖充分溶解,加入EDC(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐)和NHS(N-羟基琥珀酰亚胺),继续搅拌后得到壳聚糖醋酸溶液;
(2)TMG修饰壳聚糖的制备
取步骤(1)所得壳聚糖醋酸溶液,加入TMG(三(羟甲基)甲基甘氨酸)后搅拌,反应,反应结束后将反应产物置于透析袋中,用水透析,冻干,得到TMG修饰的壳聚糖;
(3)高粘附性壳聚糖基水凝胶的制备
将步骤(2)所得TMG修饰的壳聚糖溶于水中,缓慢搅拌后静置,得到高粘附性壳聚糖基水凝胶。
步骤(1)所述醋酸溶液的体积分数(v/v,ml/ml)为0.5%~2%;优选为1%。
步骤(1)所述壳聚糖的平均分子量为3~10Kda;优选为5Kda。
步骤(1)所述的壳聚糖的质量与醋酸溶液的体积的比为1:200~30;优选为1:100。
步骤(1)所述的1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐与壳聚糖的摩尔比为1~2:1~2;优选为1:1。
步骤(1)所述的N-羟基琥珀酰亚胺与壳聚糖的摩尔比为1~2:1~2;优选为1.2:1。
步骤(1)所述的继续搅拌为搅拌30分钟。
步骤(2)所述的反应的温度为室温。
步骤(2)所述的反应的时间为24~72h;优选为48h。
步骤(2)所述的TMG与壳聚糖的摩尔比为1~5:1;优选为3:1。
步骤(2)所述的透析采用的透析袋截留分子量为3000~4000;优选为3500。
步骤(2)所述的透析的时间为3~5天;优选为3天。
步骤(3)所述的TMG修饰的壳聚糖的质量与水的体积比(质量浓度,w/v)为1:5~30;优选为1:10。
步骤(3)所述的搅拌的转速为200r/min。
步骤(3)所述的搅拌的时间为1h。
步骤(3)所述的静置的时间为24h。
上述制备方法制备得到的高粘附性壳聚糖基水凝胶。
上述高粘附性壳聚糖基水凝胶作为医用组织粘合剂的应用。
上述高粘附性壳聚糖基水凝胶在制备粘合剂中的应用。
本发明相对于现有技术具有如下的优点及效果:
(1)本发明采用的主要原料为天然多糖壳聚糖和作为生物缓冲液的TMG,原料来源丰富,具有优良生物相容性和生物可降解性。
(2)本发明中TMG与壳聚糖进行酰胺化反应,不需外加交联剂,反应条件温和,操作简单,在生物医用上具有应用前景。
(3)本发明中采用TMG修饰壳聚糖,通过氢键交联形成水凝胶,得到以天然多糖基为原料的水凝胶。
(4)本发明中所得到的水凝胶通过与皮肤表面形成氢键作用,从而赋予水凝胶优异的粘附性能,可用于伤口敷料和急性止血材料。除皮肤表面外,本发明所得水凝胶在玻璃、金属等材料表面同样表现出优异的粘附性能,在粘合剂方面具有潜在的应用前景。
附图说明
图1是实施例1中产物的结构示意图和核磁共振氢谱谱图。
图2是实施例1中产物的傅里叶变换红外(FTIR)光谱图。
图3是实施例3中凝胶样品的扫描电镜图。
图4是实施例4中产物在应变扫频的流变数据图。
图5是实施例4中产物在频率扫描的流变数据图。
图6是实施例5中凝胶样品的溶胀程度随时间的变化曲线。
图7是实施例6中凝胶样品的失水程度随时间的变化曲线。
图8是实施例7中凝胶样品在猪皮表面的粘附强度。
图9是实施例8中凝胶样品在马口铁片、玻璃上的粘附强度。
图10是实施例9中压力爆裂实验的装置示意图。
图11是实施例9中凝胶样品的压力爆裂数据图。
图12是实施例10中凝胶样品的细胞存活率。
图13是实施例11中凝胶样品的溶血率。
图14是实施例12中凝胶样品的出血量。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
下面实施方案中若未注明具体试验条件,则通常按照常规试验条件或按照试剂公司所建议的试验条件。所使用的材料、试剂等,若无特殊说明,均为从商业途径得到的试剂和材料。
实施例1
(1)取2ml的醋酸,滴加到200ml去离子水中形成1%醋酸溶液。
(2)称取壳聚糖2.0g,加入到步骤(1)得到的溶液中,不断搅拌直至壳聚糖完全溶解。
(3)称取2.2g EDC(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐)和1.5g NHS(N-羟基琥珀酰亚胺),加入到步骤(2)得到的溶有壳聚糖的醋酸溶液中,反应30min。
(4)称取TMG(三(羟甲基)甲基甘氨酸)6g,加入到步骤(3)得到的溶液中,在室温下反应48小时。
(5)反应结束后将反应产物置于截留分子量为3500的纤维素透析袋中,用去离子水透析4天,冻干,得到TMG修饰的壳聚糖(CTMG)。
使用核磁共振检测制备得到的壳聚糖,图1为产物的核磁共振氢谱谱图,与CS相比,CTMG在3.85处出现新的质子峰,为TMG结构单元上亚甲基的特征峰,说明成功合成CTMG;产物的傅里叶变换红外(FTIR)光谱图如图2所示,1655.04、1595.86、1422.02cm-1附近的峰为壳聚糖中的酰胺官能团(CONH),与CS谱图相比,CTMG谱图在此范围内峰强度有了明显的提高,说明CS与TMG之间形成了酰胺化反应,与此同时在3360,47cm-1处有一个明显的吸收峰,且羟基的吸收峰不对称的变宽,向低波数方向移动,这是由于TMG单体聚合形成长链大分子,氢键密度增大的原因导致。实验结果证明,TMG成功修饰到壳聚糖结构上。
实施例2
按照表1称取不同质量的实施例1的产物,溶于一定体积的去离子水中,形成不同浓度的水凝胶,即高粘附性壳聚糖基水凝胶。
表1
实施例3
将实施例2得到的三种不同浓度的水凝胶冻干,真空镀金,采用FEI/OXFORD/HKL公司Quanta 400FEG场发射扫描电子显微镜观察水凝胶的断面形态。图3为所得产物的扫描形貌图,由此可知所得产物具有三维网状结构。
实施例4
取实施例2中所制得的三种水凝胶,采用英国Malvern Instruments Ltd公司的Kinexus Pro+型旋转流变仪对凝胶进行流变性能测试。
夹具为直径为25mm平行板,实验温度为25℃,平行板夹具的间距(Gap)为1mm。首先对水凝胶进行动态应变扫描,以确定水凝胶的线性粘弹范围,扫描频率固定为1rad/s,扫描范围为0.01~100%。然后对样品进行动态频率扫描,其应变固定为1%,频率的扫描范围为0.01~10Hz。
实验结果如图4~5所示,图4为水凝胶的动态应变扫描曲线,可以看出,随着CTMG浓度的增加,样品的最大线性粘弹区域应变值提高,说明浓度的增加使得体系的交联点增加,所形成的网络结构更加致密;水凝胶的动态频率扫描曲线如图5所示,15CTMG水凝胶样品的G’始终大于G”,呈现固体的性质,说明此时水凝胶已经形成了较为完善的网络结构。
实施例5
取实施例2中所制得的15CTMG水凝胶样品,冻干,在40℃的烘箱中烘干至恒重,测量烘干后的质量W0,将烘干的水凝胶样品放入加满去离子水的培养皿中,相隔一定时间将凝胶从水中取出,用滤纸吸干表面水分,称量凝胶吸水后的质量W1,计算溶胀率(Swellingratio)SR:
得到水凝胶的溶胀性能,结果如图6所示,在前30min水凝胶溶胀率急剧上升,之后趋于缓和,在达到溶胀平衡后,溶胀率高达1075%,说明水凝胶具有良好的吸水溶胀能力,适用于制备伤口敷料。
实施例6
取实施例5中达到溶胀平衡的水凝胶,吸干表面的水分,测量凝胶质量W2,把凝胶放入27℃的烘箱中,相隔一定时间取出凝胶,并称量凝胶的质量W3,计算凝胶的保水率(water retention ratio)WR:
得到水凝胶的保水性能,结果如图7所示,在前3小时水凝胶失水速度较快,之后趋于缓和,在达到平衡后,保水率为16%,说明CTMG水凝胶具有一定的保水性能。
实施例7
取实施例2中所制得的三种凝胶,采用深圳科比试验设备公司的微机控制电子万能试验机进行搭接剪切试验,以测量水凝胶在猪皮表面的粘附性能。把猪皮制成25mm×30mm的尺寸,用502胶水把猪皮紧密粘附在马口铁片上,把水凝胶均匀涂覆在两片猪皮之间,控制水凝胶的尺寸为25mm×20mm×1mm,接触面积S为5cm2,静置12小时,之后进行单轴拉伸实验,拉伸速率为0.2mm/min,得到最大拉伸应力F,由此计算水凝胶样品在猪皮上的粘附强度(adhesion strength):
得到凝胶样品在猪皮表面的粘附强度,如图8所示,与医用氰基丙烯酸酯胶水(瑞典墨尼克医疗有限公司康派特医用胶水)相比,三种水凝胶在猪皮表面表现出更加优异的粘附性能,其中10CTMG的粘附强度最高,为113.2KPa,说明CTMG水凝胶具有优异的粘附性能。
实施例8
取实施例2所制得的三种水凝胶样品,采用深圳科比试验设备公司的微机控制电子万能试验机进行搭接剪切试验,以测量水凝胶样品在不同基底材料表面的粘附性能。把基底材料裁成25mm×75mm的尺寸,通过碱洗除油,并用去离子水冲洗三次,以除去材料表面污渍。把水凝胶均匀涂覆在基底材料之间,控制水凝胶的尺寸为25mm×20mm×1mm,接触面积S为5cm2,静置12小时,之后进行单轴拉伸实验,拉伸速率为0.2mm/min,得到最大拉伸应力F,由此计算水凝胶样品在基底材料上的粘附强度(adhesion strength):
图9为三种水凝胶样品在马口铁片和玻璃上的粘附强度,说明CTMG水凝胶在玻璃、金属等材料表面同样表现出优异的粘附性能,在粘合剂方面具有潜在应用价值。
实施例9
通过压力爆裂实验来衡量水凝胶所能承受的压力大小,图10为装置示意图。猪皮表面切开2mm长的切口,取实施例2所制得的三种水凝胶样品,粘附在切口上,施加0.5KPa的压力1min,以确保水凝胶与猪皮表面完全粘附,装置处于完全密闭状态,之后以10ml/min的速度缓慢注入空气,直至水凝胶爆裂,每个样品重复试验三次。
三种水凝胶样品所能承受最大压力如图11所示,三种水凝胶样品所能承受的爆裂压力均大于医用止血海绵(江西省祥恩医疗科技发展有限公司),远高于成人正常动脉血压(0.012MPa~0.018MPa),说明所制得的三种水凝胶样品具备成为止血材料的条件。
实施例10
取实施例2所制得的水凝胶样品冻干,研磨成粉末并通过紫外照射灭菌,然后,将其分散在细胞培养液中配置成10、20、50和100、200μg/mL的溶液;收集对数期人正常肝细胞(LO2)进行CCK-8细胞毒性实验,在96孔板中分别加入1×105个对数期LO2细胞,分别加入上述不同浓度的水凝胶溶液,并设置空白对照组,在37℃恒温箱中孵育24h后,加入CCK-8染料后继续孵育2h,使用酶标仪在450nm下测量吸光度,以空白对照为基准最后计算细胞的存活率,每组进行5次平行试验。
图12为各水凝胶样品浓度下人正常肝细胞(LO2)的存活率,由图12可知,与所有浓度共培养的细胞活性均达到80%以上,表明CTMG水凝胶对LO2细胞具有较低的细胞毒性,生物相容性良好。
实施例11
取实施例2中所制得的三种水凝胶样品,冻干,通过体外溶血实验来衡量CTMG样品的血液相容性。分别将5mg的三种水凝胶冻干样品溶于3mL的PBS溶液中,并在37℃下孵育24小时,得到样品浸出液。然后将125μL的样品浸出液与875μL的2%新鲜抗凝红细胞溶液充分混合,在37℃恒温箱中孵育1小时后离心(3000rpm,10分钟),取100μL上清液转移到96孔板中,用多功能酶标仪在540nm处测量上清液的吸光度。PBS为阴性对照组,TritonX-100为阳性对照组,每个样品5个平行样。
样品的溶血率如图13所示,三种水凝胶样品的溶血率均低于5%,说明三种水凝胶样品血液相容性良好,满足临床应用的需求。
实施例12
以SD大鼠肝脏出血模型来评价CTMG凝胶和商用止血海绵的止血性能。取实施例2所制得三种水凝胶,冻干。使用10%水合氯醛溶液对SD大鼠(雌性,体重180g~220g,6周龄)进行麻醉,并将其固定在手术软板上,软木板的倾斜角度为30°;用手术刀剪开大鼠腹部暴露肝脏,小心擦拭大鼠肝脏附近的体液,将一张质量为W0的滤纸置于肝脏下方,使用手术刀在肝脏表面制造长10mm,深5mm的伤口,分别将7CTMG、10CTMG、15CTMG水凝胶冻干样品置于伤口上,每隔30s观察伤口的出血情况。当出血停止时,称量吸收血液后的滤纸重量W1。空白对照组对伤口不施加任何材料,阳性对照组穿刺伤口后采用医用止血海绵(江西省祥恩医疗科技发展有限公司)作为敷料。
CTMG凝胶和医用止血海绵的出血量如图14所示,与医用止血海绵相比,CTMG凝胶具有良好的止血效果,说明所制得的三种水凝胶样品具备成为止血材料的条件。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.一种高粘附性壳聚糖基水凝胶的制备方法,其特征在于包括如下步骤:
(1)壳聚糖醋酸溶液的制备
将壳聚糖溶于醋酸溶液中,搅拌,使壳聚糖充分溶解,加入EDC(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐)和NHS(N-羟基琥珀酰亚胺),继续搅拌后得到壳聚糖醋酸溶液;
(2)TMG修饰壳聚糖的制备
取步骤(1)所得壳聚糖醋酸溶液,加入TMG(三(羟甲基)甲基甘氨酸)后搅拌,反应,反应结束后将反应产物置于透析袋中,用水透析,冻干,得到TMG修饰的壳聚糖;
(3)高粘附性壳聚糖基水凝胶的制备
将步骤(2)所得TMG修饰的壳聚糖溶于水中,缓慢搅拌后静置,得到高粘附性壳聚糖基水凝胶。
2.根据权利要求1所述的制备方法,其特征在于:
步骤(1)所述醋酸溶液的体积分数为0.5%~2%;
步骤(1)所述的壳聚糖的质量与醋酸溶液的体积的比为1:200~30。
3.根据权利要求1所述的制备方法,其特征在于:
步骤(1)所述的EDC与壳聚糖的摩尔比为1~2:1~2;
步骤(1)所述的NHS与壳聚糖的摩尔比为1~2:1~2。
4.根据权利要求1所述的制备方法,其特征在于:
步骤(2)所述的TMG与壳聚糖的摩尔比为1~5:1。
5.根据权利要求1所述的制备方法,其特征在于:
步骤(2)所述的反应的温度为室温;
步骤(2)所述的反应的时间为24~72h;
步骤(2)所述的透析采用的透析袋截留分子量为3000~4000;
步骤(2)所述的透析的时间为3~5天。
6.根据权利要求1所述的制备方法,其特征在于:
步骤(3)所述的TMG修饰的壳聚糖的质量与水的体积比为1:5~30。
7.根据权利要求1所述的制备方法,其特征在于:
步骤(3)所述的搅拌的转速为200r/min;
步骤(3)所述的搅拌的时间为1h;
步骤(3)所述的静置的时间为24h。
8.一种高粘附性壳聚糖基水凝胶,其特征在于根据权利要求1~7任一所述的制备方法制备得到。
9.权利要求8所述的高粘附性壳聚糖基水凝胶作为医用组织粘合剂的应用。
10.权利要求8所述的高粘附性壳聚糖基水凝胶在制备粘合剂中的应用。
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